CN106389328B - A kind of injection prostadil fatty cream - Google Patents
A kind of injection prostadil fatty cream Download PDFInfo
- Publication number
- CN106389328B CN106389328B CN201510463274.9A CN201510463274A CN106389328B CN 106389328 B CN106389328 B CN 106389328B CN 201510463274 A CN201510463274 A CN 201510463274A CN 106389328 B CN106389328 B CN 106389328B
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- Prior art keywords
- injection
- oil
- phosphatidyl
- phosphatidyl choline
- added
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Abstract
The present invention provides a kind of injection prostadil fatty cream; include Alprostadil, phosphatidyl choline, phosphatidyl glycerol; oil for injection; freeze drying protectant, wherein the weight proportion of each component is as follows, and the weight of Alprostadil is 1 part; the weight of oil for injection is 2000-8000 parts; the amount of phosphatidyl choline is 1200-2400 parts, and the weight of phosphatidyl glycerol is 1-9 parts, and the amount of freeze drying protectant is 12000-24000 parts.The injection prostadil fatty cream not only increases the stability of drug and freeze-drying front and back partial size, and the freeze-drying prods physical aspect obtained is more preferable.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of injection prostadil fatty cream.
Background technique
Alprostadil injection is listed in Japan at first, Fat Emulsion drug delivery technologies is used, by drug, soybean oil, purification
Egg yolk lecithin, oleic acid, glycerol and pH adjusting agent composition, preparation method is that drug is dissolved in fat oil, to refine lecithin
Rouge is emulsifier, and oleic acid is coemulsifier, and O/W type drug-loaded emulsion, milk particle average grain diameter 200nm is made through high-pressure homogeneous.
Alprostadil injection greatly reduces irritating generation by drug encapsulation in oily phase using the load prescription formula of Fat Emulsion.
It has the advantage that (1) targeting: it is higher to the affinity of inflammation part vascular wall, it can be in atherosclerotic blood vessel, height
It is deposited on blood pressure vascular wall, plays curative effect for diseased region, and the influence to normal blood vessels is seldom, substantially reduces side reaction hair
Raw rate, is known as " drug guided missile ".(2) long-term effect: the Half-life in vivo of the common powder-injection of Alprostadil only 3~5 minutes, by it
After lipid microspheres are made, 12~24 hours release drugs can be maintained, play drug effect.(3) highly effective and safe: prostadil fatty cream
Quantity is only the 1/5~1/10 of traditional powder injection formulation, that is, can reach better therapeutic effect；Alprostadil adverse reaction hair
Raw rate is only the 1/10 of traditional powder injection formulation.
Since alprostadil injection exists in the form of an emulsion, still some drug can meet water and degrade, and produce
Raw following quality problems: (1) the catabolite PGA of alprostadil injection1Content be up to 60% (national standard WS1- (X-
041)-2002Z-2008)；(2) validity period is short, and only 12 months (0~5 DEG C).
For this purpose, alprostadil injection has been done further improvement, sterile freeze-drying preparation-note is made in its dosage changing form
It penetrates and uses prostadil fatty cream, reduce contact of the drug with water, increase its stability.Commercialized product is Chongqing medicine friend at present
The injection Alprostadil dried emulsifier of production, main component are lactose, egg yolk lecithin, sodium citrate, enuatrol, soybean oil
And glycerol, the validity period saved in the cool (less than 20 DEG C) also only have 12 months.
Patent document CN1562041 discloses a kind of freeze-drying Alprostadil emulsions and preparation method thereof, containing forefront
You, oil for injection, emulsifier, stabilizer, glycerol, preservative, pH range is 4~9, and the patent document is with disclosing forefront
Your freeze-dried emulsion has used nonionic surfactant other than using phosphatide, poloxamer, and tween etc. is prepared
Product is completely inconsistent with this product.
Patent document CN1903206 discloses a kind of Alprostadil freeze-dried emulsion and preparation method thereof, every 1000 milliliters of creams
The weight percent of pharmaceutic adjuvant is in agent, oil for injection 0.01~1%, and emulsifier 0.01~5%, freezes stabilizer 1~6%
Dry protective agent 1%~20%；PH range 4~9 (pH range 4.21~5.43 in embodiment).It studies discovery Alprostadil lotion
Stability it is excessively poor, not only glucide cannot be guaranteed not to be demulsified in process of production, meanwhile, carbohydrate freeze drying protectant is answered
Newborn effect is not up to the requirement of micro-emulsion injecta.It uses human serum albumin and glucide to share the system for solving freeze-dried emulsion
Standby, prepared 50~600nm of freeze-dried emulsion particle size range.Human serum albumin although the problem of can solve frozen-dried protective,
Its limited source, it is expensive, it is unsuitable for the wide clinical application of the product.
In patent document CN201010168597.2 to solve this problem, using cyclodextrin substance and glucide one
It rising and does the stability that freeze drying protectant increases drug, principle, which is cyclodextrin, wraps up drug and increases stability, just not saying ring
Dextrin itself has certain renal toxicity and hemolytic for being injected intravenously, and concentrates the talk of after cyclodextrin wraps up drug, increases water-soluble
Property, drug will be distributed in water phase with bigger ratio in oily phase, and therefore, there are hidden danger in terms of preparation security.
CN201310573326.9 to solve this problem, is done jointly in certain proportion using specific amino acid and glucide and is frozen
Dry protective agent.CN201310603102.8 improves stability by the way of vitamin E is added in prescription.
CN201410440057.3 discloses a kind of Alprostadil freeze-dried cream, includes Alprostadil, phosphatidyl choline, phosphatide
Acyl inositol, oil for injection, freeze drying protectant, weight proportion is as follows, and the weight of Alprostadil is 1 part, the weight of oil for injection
It is 2000~20000 parts, the amount of emulsifier is 400-4000 parts, and the weight of phosphatidylinositols is 12-120 parts, freeze drying protectant
Amount be 6000-60000 parts.Prepared stable product quality is more preferable, and encapsulation rate improves, and front and back milk particle is lyophilized does not have
Significant change.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of injection prostadil fatty creams.
Technical scheme is as follows:
A kind of injection prostadil fatty cream, includes Alprostadil, phosphatidyl choline, phosphatidyl glycerol, oil for injection,
Freeze drying protectant, weight proportion therein is as follows, and the weight of Alprostadil is 1 part, and the weight of oil for injection is 2000-8000
Part, the weight of phosphatidyl choline is 1200-2400 parts, and the weight of phosphatidyl glycerol is 1-9 parts, and the weight of freeze drying protectant is
12000-24000 parts.
Preferably the weight of Alprostadil is 1 part, and the weight of oil for injection is 4000-8000 parts, the weight of phosphatidyl choline
Amount is 2000-2400 parts, and the weight of phosphatidyl glycerol is 3-7 parts, and the weight of freeze drying protectant is 14000-18000 parts.
The phosphatidyl choline is selected from the phosphorus extracted in natural phosphatidyl choline and its salt such as yolk
Phosphatidylcholine and its salt, phosphatidyl choline and its salt of synthesis or combinations thereof.Wherein the phosphatidyl choline of the synthesis is selected from two
Stearoyl phosphatidyl choline (DSPC), dioleyl phosphatidyl choline (DOPC), Dioctonoyl pnosphotidyl choline (DPPC),
L-Dimyristoylphosphatidylcholine (DMPC), Dinonyl Phosphatidylcholine DDPC, Dilauroyl Phosphatidylcholine
(DLPC), two mustard phosphatidyl choline (DEPC), 1- stearyl -2- oleolyl phosphatidyl choline (SOPC), 1- palmityl
Base -2- oleolyl phosphatidyl choline (POPC), 1- myristoyl -2- oleolyl phosphatidyl choline (MOPC), 1- stearyl -
2- palmityl phosphatidyl choline (SPPC), 1- stearyl -2- myristoyl phosphatidyl choline (SMPC), 1- palmityl
Base -2- stearoyl phosphatidyl choline (PSPC), 1- palmityl -2- myristoyl phosphatidyl choline (PMPC), 1- Pork and beans
Cool acyl group -2- stearoyl phosphatidyl choline (MSPC), 1- myristoyl -2- palmityl phosphatidyl choline (MPPC) or its
Combination.
The phosphorus that the phosphatidyl glycerol (PG) extracts in natural phosphatidyl glycerol and its salt such as yolk
Phosphatidyl glycerol and its salt, phosphatidyl glycerol and its salt of synthesis or combinations thereof.Wherein the phosphatidyl glycerol of the synthesis is selected from two
Stearoyl phosphatidyl glycerol (DSPG), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG),
Dimyristoylphosphatidylglycerol (DMPG), 1- palmityl -2- oleolyl phosphatidyl glycerol (POPG), two mustard acyl phosphatidyls
Glycerol (DEPG), dilauroylphosphatidylglycerol (DLPG) or combinations thereof.
The oil for injection be selected from refined soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil,
Fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol are double
Ester, glyceryl linoleate, polyethylene glycol glyceryl laurate ester or combinations thereof, preferably olive oil, more preferably olive oil are in
Chain triglyceride, the two weight ratio are 1:1.
The freeze drying protectant is selected from lactose, sucrose, trehalose, dextran or combinations thereof.
There are also pH adjusting agent, pH adjusting agents to select hydrochloric acid solution or hydrogen-oxygen for injection prostadil fatty cream of the invention
Change sodium solution.
The present invention provides a kind of preparation method of injection prostadil fatty cream, comprising the following steps:
(1) preparation of water phase: freeze drying protectant being added in water for injection, is stirred to dissolve, and phosphatidyl choline is added
High speed shear dispersion, as water phase；
(2) preparation of oily phase: phosphatidyl glycerol and Alprostadil are added in oil for injection, stirs evenly, as oily phase；
(3) preparation of colostrum: step (2) oil is added in step (1) water phase, and high speed shear dispersion forms colostrum；
(4) high-pressure homogenising: it is high-pressure homogenising by step (3) colostrum, obtain smart cream；
(5) sterile filling: by step (4) essence cream through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating is into cillin bottle；
(6) be freeze-dried: by sample vacuum freeze drying in step (5) cillin bottle to get.
High speed shear jitter time described in step (3) is 10~60 minutes, and shear velocity is 3000~10000rpm, temperature
55~70 DEG C of degree；High-pressure homogenising pressure described in step (4) is 600~2000bar, homogenizes number 3~6 times, temperature 15~30
℃.Vacuum freeze drying described in step (6) is that sample is rapidly frozen to temperature -50~-45 DEG C, is maintained 1~3 hour；One
- 35~-30 DEG C of secondary drying temperature, the primary drying time 24~48 hours；25~40 DEG C of redrying temperature, the redrying time
2~6 hours.
Compared with prior art, the present invention is using phosphatidyl glycerol as coemulsifier, phosphatidyl glycerol and phosphatidyl
Mutually there is apparent influence with the physical aspect for comparing freeze-drying prods between choline, oil for injection and freeze drying protectant, because
This, the present invention further obtains physical aspect more while change of size before and after solving medicine stability and freeze-drying
The dry cream of good prostadil fatty junket.
Specific embodiment
Embodiment 1
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Embodiment 2
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Embodiment 3
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Embodiment 4
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Embodiment 5
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Comparative example 1
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Comparative example 2
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Comparative example 3
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Comparative example 4
Prescription:
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, yolk phosphatidylglycerol (EPG, Shanghai Ai Wei is added
It is special) high speed shear dispersion, Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum tune pH to 6.9~7.1, high-pressure homogenising 3 times through microjet instrument, pressure
1000~1200bar；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
The average grain diameter and particle diameter distribution of 1 milk particle of testing example
Inspection method: Dynamic laser scattering particle size determination method
Specific test operation: taking this product 0.1ml before freeze-drying, purified water is added (to filter) dilution with the film in 0.22 μm of aperture in advance
It 5000 times, mixing, as test liquid, is measured with Dynamic laser scattering particle size determination method, the average grain diameter of milk particle should be 0.12~
0.28μm。
It is measured after sample is first redissolved with water for injection after freeze-drying according to aforesaid operations.
Testing result:
The result shows that embodiment 1-5, comparative example 1-4 freeze-drying front and back partial size and changes in distribution are all pharmaceutically acceptable
In range, but present inventors have unexpectedly found that, when the ratio of each component exceeds a certain range in prescription, freeze-drying prods lower part occurs
Atrophy phenomenon.
The physical aspect of freeze-drying prods is an important indicator of freeze-drying prods.Good freeze-drying prods should have good object
Form, appearance N/D, surfacing, volume and of substantially equal when freezing, color uniformity are managed, loose and porous inner surface is multiple
Water is rapid and complete.The present invention passes through the content for limiting each component in prescription, thus before obtaining the better injection of effect
Column ground that Fat Emulsion.
Embodiment 6
Technique:
(1) preparation of water phase: being added to the water dissolution for sucrose and trehalose, is heated to 65 DEG C, and DMPC high speed shear is added
Dispersion, it is spare；
(2) preparation of oily phase: being heated to 65 DEG C for refined soybean oil, and the dispersion of DMPG high speed shear is added, forefront is added
You, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum high-pressure homogenising 3 times through microjet instrument, 1000~1200bar of pressure；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Average grain diameter is 189nm after freeze-drying, and freeze-drying prods are that white loose is blocky.
Embodiment 7
Technique:
(1) preparation of water phase: being added to the water dissolution for lactose, is heated to 65 DEG C, be added phosphatidyl choline (PC-98T, on
Hai Aiweite) high speed shear is dispersed, spare；
(2) preparation of oily phase: refined soybean oil is heated to 65 DEG C, distearoylphosphatidylglycerol sodium (Shang Haidong is added
Still) high speed shear is dispersed, and Alprostadil is added, stirs to dissolve；
(3) preparation of colostrum: step (2) oil being added in step (1) water phase, 65 DEG C of temperature, and high speed shear dispersion is cut
Cutting speed degree 10000rpm the time 15 minutes, forms colostrum；
(4) high-pressure homogenising: by step (3) colostrum high-pressure homogenising 3 times through microjet instrument, 1000~1200bar of pressure；
(5) initial filter: by step (4) essence cream through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered: emulsion is made through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating in step (5)；
(7) it is freeze-dried: sample is rapidly frozen to -45 DEG C of temperature by sample vacuum freeze drying obtained by step (6),
- 35 DEG C are warming up to, is maintained 3 hours；- 30 DEG C of primary drying temperature, the primary drying time 24 hours；30 DEG C of redrying temperature,
6 hours redrying time is to get injection prostadil fatty cream.
Average grain diameter is 190nm after freeze-drying, and freeze-drying prods are that white loose is blocky.
2 study on the stability of testing example
The sample of above-mentioned preparation is placed under the conditions of 40 DEG C, at the 10th day, 30 days sampling and measuring contents, with 0 day contain
Amount is reference, calculates content decline percentage (%).
Content assaying method: post-column derivation+HPLC method
Chromatographic condition:
Chromatographic column: C18Column (model: YMC；250 × 4.6mm, 5 μm)
Mobile phase: 0.0067mol/L phosphate buffer (pH 6.3) (potassium dihydrogen phosphate 9.07g is taken, water is added to make to dissolve,
1000ml is made, separately takes Anhydrous Disodium Phosphate 9.46g, adds water to make to dissolve, 1000ml is made, the latter is added in the former, directly
To pH be 6.3, take this liquid 100ml to add water to 1000ml, shake up to get)-acetonitrile (3:1).
Sample volume: 20 μ l；Flow velocity: 1.0ml/min；Detection wavelength: 278nm；Column temperature: 60 DEG C
Past column reaction pipe: polyfluortetraethylene pipe
Past column reaction liquid: 1mol/L potassium hydroxide solution
React flow velocity: 0.5ml/min
Test result:
Content decline percentage (%) under the conditions of 40 DEG C
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| 10 days | 1.3% | 1.7% | 2.0% | 1.7% | 1.6% | 1.4% | 1.2% |
| 30 days | 3.5% | 4.4% | 4.7% | 4.0% | 4.6% | 4.2% | 4.7% |
The result shows that sample of the present invention has good stability.
3 encapsulation rate of testing example
Encapsulation rate is measured using low temperature supercentrifugation
Assay of the drug in water phase
Using two step centrifugal process, this product is taken, water for injection is added to redissolve the solution at 50~100 μ g/ml, is placed in low temperature hypervelocity
In centrifuge, set temperature is 25 DEG C, adjusts revolving speed for the first time to 5000rpm, is respectively placed in the centrifugation of 10mL centrifuge tube high speed
3h takes out, careful to draw lower layer's solution (thin lotion) in right amount, is respectively placed in low temperature ultracentrifuge, and second of adjusting turns
Speed is 8000rpm, continues to be centrifuged 1h, until lower layer is clear aqueous solution, same aforesaid operations draw lower layer's clear aqueous solution respectively,
It is filtered with 0.22 μm of miillpore filter, takes subsequent filtrate, according to method under content determination item, measure content of the drug in water phase.
The measurement of total drug content
According to the measuring method measurement under 1 content determination item of test case, the as a result as total drug content of this product.
The calculating of encapsulation rate
Content due to drug in oil, oil-water interfaces is difficult to measure, and the encapsulation rate of this product such as following formula calculates to obtain the final product.
Measurement result
Above-mentioned sample is taken, is detected according to said determination method.
| Embodiment | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Encapsulation rate | 94.2% | 94.7% | 96.0% | 96.7% | 95.6% | 96.2% | 96.4% |
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can
No further explanation will be given for the combination of energy.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (11)
1. a kind of injection prostadil fatty cream includes Alprostadil, phosphatidyl choline, phosphatidyl glycerol, oil for injection, jelly
Dry protective agent, wherein the weight proportion of each component is as follows, and the weight of Alprostadil is 1 part, and the weight of oil for injection is 2000-
8000 parts, the amount of phosphatidyl choline is 1200-2400 parts, and the weight of phosphatidyl glycerol is 1-9 parts, and the amount of freeze drying protectant is
12000-24000 parts.
2. injection prostadil fatty cream according to claim 1, which is characterized in that the weight of Alprostadil is 1 part,
The weight of oil for injection is 4000-8000 parts, and the amount of phosphatidyl choline is 2000-2400 parts, and the weight of phosphatidyl glycerol is 3-7
Part, the amount of freeze drying protectant is 14000-18000 parts.
3. injection prostadil fatty cream according to claim 1 to 2, which is characterized in that the phosphatidyl gallbladder
Alkali is selected from natural phosphatidyl choline and its salt, phosphatidyl choline and its salt of synthesis or combinations thereof.
4. injection prostadil fatty cream according to claim 3, which is characterized in that the phosphatidyl gallbladder of the synthesis
Alkali is selected from distearoyl phosphatidylcholine, dioleyl phosphatidyl choline, Dioctonoyl pnosphotidyl choline, two myristoyls
Base phosphatidyl choline, Dinonyl Phosphatidylcholine, Dilauroyl Phosphatidylcholine, two mustard phosphatidyl cholines, 1- are hard
Fatty acyl group -2- oleolyl phosphatidyl choline, 1- palmityl -2- oleolyl phosphatidyl choline, 1- myristoyl -2- oleoyl
Phosphatidyl choline, 1- stearyl -2- palmityl phosphatidyl choline, 1- stearyl -2- myristoyl phosphatidyl choline,
1- palmityl -2- stearoyl phosphatidyl choline, 1- palmityl -2- myristoyl phosphatidyl choline, 1- myristoyl
Base -2- stearoyl phosphatidyl choline, 1- myristoyl -2- palmityl phosphatidyl choline or combinations thereof.
5. injection prostadil fatty cream according to claim 1 to 2, which is characterized in that the phosphatidyl is sweet
Oil is selected from natural phosphatidyl glycerol and its salt, phosphatidyl glycerol and its salt of synthesis or combinations thereof.
6. injection prostadil fatty cream according to claim 5, which is characterized in that the phosphatidyl of the synthesis is sweet
Oil is selected from distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, two myristoyls
Base phosphatidyl glycerol, 1- palmityl -2- oleolyl phosphatidyl glycerol, di-mustard phosphatidyl glycerol, two lauroyl phosphatidyls are sweet
Oil or combinations thereof.
7. injection prostadil fatty cream according to claim 1 to 2, which is characterized in that the oil for injection
Selected from refined soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil, fish oil, medium chain mono, middle chain
Diglyceride, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, poly- second two
Alcohol glyceryl laurate ester or combinations thereof.
8. injection prostadil fatty cream according to claim 7, which is characterized in that the oil for injection is olive
Oil.
9. injection prostadil fatty cream according to claim 7, which is characterized in that the oil for injection is olive
Oil and medium chain triglyceride, the two weight ratio are 1:1.
10. injection prostadil fatty cream according to claim 1 to 2, which is characterized in that the freeze-drying is protected
It protects agent and is selected from lactose, sucrose, trehalose, dextran or combinations thereof.
11. the preparation method of any injection prostadil fatty cream of claim 1-10, comprising the following steps:
(1) preparation of water phase: freeze drying protectant being added in water for injection, is stirred to dissolve, and phosphatidyl choline high speed is added
Shearing dispersion, as water phase；
(2) preparation of oily phase: phosphatidyl glycerol and Alprostadil are added in oil for injection, stirs evenly, as oily phase；
(3) preparation of colostrum: step (2) oil is added in step (1) water phase, and high speed shear dispersion forms colostrum；
(4) high-pressure homogenising: it is high-pressure homogenising by step (3) colostrum, obtain smart cream；
(5) sterile filling: by step (4) essence cream through 0.22 μm of filtering with microporous membrane degerming, sterile encapsulating is into cillin bottle；
(6) be freeze-dried: by sample vacuum freeze drying in step (5) cillin bottle to get.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511367A (en) * | 2006-09-05 | 2009-08-19 | 丘比株式会社 | Prostaglandin fat emulsion, method for producing the same, method for stabilizing the same, and emulsifying agent |
| CN103301076A (en) * | 2012-03-13 | 2013-09-18 | 辽宁诺康生物制药有限责任公司 | Alprostadil frozen-drying lipid emulsion and preparation method thereof |
| CN103961356A (en) * | 2013-01-24 | 2014-08-06 | 上海医药工业研究院 | Freeze-dried alprostadil composition for injection and preparation method thereof |
| CN104173301A (en) * | 2014-08-29 | 2014-12-03 | 北京蓝丹医药科技有限公司 | Alprostadil freeze-drying cream and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511367A (en) * | 2006-09-05 | 2009-08-19 | 丘比株式会社 | Prostaglandin fat emulsion, method for producing the same, method for stabilizing the same, and emulsifying agent |
| CN103301076A (en) * | 2012-03-13 | 2013-09-18 | 辽宁诺康生物制药有限责任公司 | Alprostadil frozen-drying lipid emulsion and preparation method thereof |
| CN103961356A (en) * | 2013-01-24 | 2014-08-06 | 上海医药工业研究院 | Freeze-dried alprostadil composition for injection and preparation method thereof |
| CN104173301A (en) * | 2014-08-29 | 2014-12-03 | 北京蓝丹医药科技有限公司 | Alprostadil freeze-drying cream and preparation method thereof |
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